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A Consensus Statement: Meningococcal Disease Among Infants, Children and Adolescents in Latin America
A Consensus Statement: Meningococcal Disease Among Infants, Children and Adolescents in Latin America
A Consensus Statement: Meningococcal Disease Among Infants, Children and Adolescents in Latin America
Ricardo Walter Rttimann, MD,* Angela Gentile, MD, Mercedes Macias Parra, MD, Xavier Saez-Llorens, MD, Marco Aurelio Palazzi Safadi, MD, PhD, and Maria Elena Santolaya, MD
Abstract: Invasive meningococcal disease is a serious infection that occurs worldwide. Neisseria meningitidis remains one of the leading causes of bacterial meningitis in all ages. Despite the availability of safe and effective vaccines against invasive meningococcal disease, few countries in Latin America implemented routine immunization programs with these vaccines. The Americas Health Foundation along with Fighting Infectious Disease in Emerging Countries recently sponsored a consensus conference. Six experts in infectious diseases from across the region addressed questions related to this topic and formulated the following recommendations: (1) standardized passive and active surveillance systems should be developed and carriage studies are mandatory; (2) a better understanding of the incidence, case fatality rates and prevalent serogroups in Latin America is needed; (3) countries should make greater use of the polymerase chain reaction assays to improve the sensitivity of diagnosis and surveillance of invasive meningococcal disease; (4) vaccines with broader coverage and more immunogenicity are desirable in young infants; (5) prevention strategies should include immunization of young infants and catch-up children and adolescents and (6) because of the crowded infant immunization schedule, the development of combined meningococcal vaccines and the coadministration with other infant vaccines should be explored. Key Words: meningococcal disease, meningitis, surveillance, epidemiology, immunization (Pediatr Infect Dis J 2014;33:284290)
a routine meningococcal vaccination program with conjugated MenC and outer-membrane protein B vaccines. Although a few other nations in the region have meningococcal vaccination programs, those available are focused only on high risk groups and/or for controlling sporadic outbreaks. To assess the current epidemiology and surveillance status of IMD disease in Latin America as well as to determine how best to protect the population from future outbreaks, the Americas Health Foundation and Fighting Infectious Diseases in Emerging Countries, recently sponsored a consensus conference to provide clarity and recommendations on these issues and to discuss how best to use public health resources and available vaccines to reduce the incidence of disease. A panel of 6 experts in infectious diseases (the authors of this article) from across the region conducted a comprehensive literature review to identify articles that (1) were published from 20002013, (2) covered aspects of meningococcal disease in Latin America and/or national and international guidelines for IMD disease prevention, (3) were based on clinical trials or were observational studies and (4) provided a clear and complete protocol as well as a description of the population studied. With this evidence base, the panel discussed the issues identied above and developed a consensus document. The present report details the panels response to six questions, which are explained below.
nvasive meningococcal disease (IMD) is a serious infection that occurs worldwide, causing about 500,000 cases and 50,000 deaths yearly. Neisseria meningitidis remains one of the leading causes of bacterial meningitis in all ages. To assess the epidemiology and disease burden of IMD, the national and regional surveillance systems are critical, since the epidemiology of IMD in Latin America has not been well-characterized and marked differences occur among countries.1 Moreover, information is not uniform and the quality of the reported data is poor in many countries. Despite the availability of safe and effective vaccines against IMD, few countries in the region have decided to implement a nationwide, routine immunization program with these vaccines. After several outbreaks, only Brazil and Cuba have implemented
Accepted for publication December 2, 2013. From the *Fighting Infectious Diseases in Emerging Countries (FIDEC), University of Miami, Miami, FL; Hospital de nios de Buenos Aires. Buenos Aires, Argentina; Comit Nacional de Inmunizaciones, Ciudad de Mxico, Mxico; Hospital del nio de Panam. Ciudad de Panam, Panam; Faculdade de Cincias Mdicas da Santa Casa, Sao Paulo, Brasil; and Hospital de nios Luis Calvo Mackenna. Facultad de Medicina, Universidad de Chile, Santiago, Chile. This study was supported by unrestricted grant from Americas Health Foundation. The authors have no other funding or conicts of interest to disclose. Address for correspondence: Ricardo Walter Rttimann, MD, 2050 Coral Way, Suite 407 Miami, FL 33145. E-mail: rruttimann@FIDEC-online.org. Copyright 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3303-0284 DOI: 10.1097/INF.0000000000000228
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The Pediatric Infectious Disease Journal Volume 33, Number 3, March 2014
has proven to be an important tool for surveillance (PCR) and to increase the accuracy of the diagnosis of bacterial meningitis used as a clinical tool (RT-PCR).69 In some developed countries like the United Kingdom, PCR is a routine diagnostic modality for patients with meningitis, with >50% of laboratory-identied meningococcal cases conrmed by PCR alone.10 The value of RT-PCR when incorporated into routine public health in Latin America was demonstrated in So Paulo, Brazil showing an increase in the diagnostic yield of bacterial meningitis by 85% over what was estimated by culture alone.11 In that study, the main risk factor for being culture negative and RT-PCR positive was prior antibiotic treatment. Results of other prospective, active surveillance systems in Mexico,12,13 where a higher meningococcal incidence rate compared with previous published information was documented, reinforce the importance of a wider adoption of PCR into routine microbiological laboratory surveillance. Although progress has been made, the panel believes that there is a clear need for better surveillance systems across the region. The establishment of sentinel-based active surveillance systems, along with passive systems, incorporating populationbased data and an expanded use of molecular-based diagnostic techniques, will be crucial to ensure accurate estimates of disease burden.
this age group. While overall there has been a downward trend in disease incidence within the region during the last few years, inconsistencies in the quality of information suggest that the disease has been underestimated. Many IMD cases in Latin America are caused by serogroups B and C, but the emergence of serogroups W and Y has been reported in some South American countries. Serogroup A disease is now rare in the region. In 1993, Pan American Health Organization implemented a Latin American and Caribbean laboratory-based passive surveillance program, named SIREVA, initially for cases of invasive S. pneumoniae infection. This network was extended in 2000 to cases of N. meningitidis; SIREVA performs a standardized systematic analysis of isolates recovered by the epidemiological survey network from countries in the region.4 Of note, not all countries participate in SIREVA and some are more active than others (Fig.1). Serogroup distribution by region or country highlights the high diversity observed across Latin America in the last years.5 Two examples of the dynamism of serogroup prevalence were seen in Colombia and in the Southern Cone. In Colombia, serogroup Y rst emerged in 2003, and 3 years later was causing almost half of all infections. In 2007, serogroup W was causing <10% of the cases in Argentina and Chile. By 2012, this serogroup was the leading cause of invasive disease across all ages in both countries.22,23 The mechanisms that contribute to dynamic meningococcal epidemiology are related to microbial, host and environmental factors. An important microbial factor is capsular switching that is the mechanism by which N. meningitidis can change its capsular phenotype, as occurred with W, as mentioned above. Meningococcal outbreaks can also be started or sustained by capsular switching.
WHAT ARE THE AVAILABLE VACCINES FOR THE PREVENTION OF MENINGOCOCCAL DISEASE?
The development of meningococcal vaccines began in the 1960s with the most signicant progress taking place during the past decade. Vaccines are now available against all meningococcal strains related to serogroups A, C, Y and W. Regarding protection against serogroup B, vaccines are available for specic strains and a broadly protective serogroup B recombinant vaccine has recently been approved in Europe and Australia.
Types of Vaccines
1. Capsular polysaccharide vaccines. These vaccines for serogroups A, C, Y and W are available in mono- and polyvalent formulations. They proved to be safe and effective in controlling outbreaks and epidemics. However, their immunogenicity in infants and young children is limited, especially against serogroup C, they exert only transitory and incomplete, if any, effect in reducing the colonization and the transmission of the meningococci in the vaccinated population and convey hyporesponsiveness after repeated doses compared with glycoconjugate vaccines. Therefore, these vaccines have been increasingly abandoned in the pediatric population. 2. Glycoconjugate vaccines. These vaccines are produced by coupling capsular polysaccharides to carrier proteins.24 These conjugate vaccines elicit a higher antibody response than polysacharide vaccines and generate antibodies that have greater functional activity. There are 2 meningococcal monovalent glycoconjugate vaccine formulations. One against serogroup A (currently being used in Africa) manufactured by Serum Institute of India and another against serogroup C, manufactured by 3 different
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FIGURE 1. Laboratory-based Surveillance of Meningococcal Disease in Latin America and Caribbean Countries, SIREVA II 20062010.*Adapted from rapid changing in trends of meningococcal disease in Brazil from 2000 to 2010, Ana Paula Silva Lemos, Maria Cecilia Outeiro Gorla, Marta Galhardo, Conceicao Martins Zanelato, Maria Vaneide de Paiva, Marcelle Vicoso dos Santos and Maria Cristina de Cunto Brandileone. National Reference Laboratory for Meningitis, Bacteriology Branch, Adolfo Lutz Institute, Sao Paulo. pharmaceutical companies (Novartis, Pzer and Baxter), all proved to be safe and immunogenic in infants. One of the vaccines, conjugated to tetanus toxoid, appears to generate higher antibody titers than the others and may result in better priming and antibody persistence.25 Recently, a bivalent meningococcal polysaccharide protein conjugate vaccine that provides protection against meningococcal serogroups C and Y along with H. inuenzae type b (Hib) was licensed in the United States for use as primary vaccination at 2-4-6 months with a booster dose in the 2nd year of life. Another bivalent HiB-MenC is used as a booster in the 2nd year of life in the United Kingdom. Finally, there are quadrivalent vaccines against serogroups A, C, Y and W. Three glycoconjugate quadrivalent vaccines are available in Latin America. One is conjugated with denatured diphtheria toxoid (MenACYW-D) and is indicated for use in individuals 9 months to 55 years. The other vaccine is conjugated with a cross-reactive, nontoxic mutant of diphtheria toxoid (MenACYWCRM197) and is indicated in Latin America for those >2 years of age.26,27 More recent clinical evidence, which included a Latin American population, suggests MenACWY-CRM197 is immunogenic from 2 months of age; this vaccine is already approved for infants in the United States.28 There is also a quadrivalent vaccine conjugated to tetanus toxoid approved in Europe for children from 1 year of age and was recently introduced in Chile, together with the other 2 quadrivalent conjugated formulations, for outbreak control. With the availability of these quadrivalent vaccines, we now have the ability to vaccinate individuals at various young ages. The panel believes that all factors considered (eg, immunogenicity, safety, epidemiology of IMD) should vaccines be approved in Latin America in individuals as young as age 2 months, this change may make them the vaccines of choice. 3. Serogroup B vaccines. Tailor-made serogroup B vaccines have been developed, which are effective against outbreaks. These protein-based vaccines developed mainly with the immunodominant outer-membrane protein called porin A, which is retained in the outer-membrane vesicle (OMV).29 This approach has been used to develop 3 different tailor-made vaccines to successfully control meningococcal B outbreaks caused by homologous strains in Cuba, New Zealand and Norway. The main limitation of OMV-B vaccines is their strain-specic response and inability to generate bactericidal antibodies against heterologous strains, particularly in infants.30,31 There has been much research to develop serogroup B vaccines based on other subcapsular proteins that will be broadly protective. By a technique known as reverse vaccinology, a vaccine has been developed that contains 3 recombinant proteins, factor H 2013 Lippincott Williams & Wilkins
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binding protein, Neisserial adhesin A and Neisseria heparin binding protein, which together are collectively expressed in the vast majority of serogroup B strains are immunogenic and elicited bactericidal activity. A four-component vaccine comprising the 3 previously mentioned proteins plus a detoxied OMV from a specic meningococcal B strain (NZ 98/254) has been developed. This 4CMenB vaccine was recently licensed for commercial distribution in Europe and Australia and has been found to be safe and immunogenic in a Latin American adolescent population.32 Another recombinant, investigational, vaccine containing 2 factor H binding protein variants, expressed as lipoproteins in Escherichia coli, has been shown to be highly immunogenic in humans and to elicit broadly reactive anti-MenB bactericidal antibodies in phase 2 clinical trials in adolescents.33 In general, meningococcal vaccines can be administered concomitantly; however, they must be injected into different sites and not mixed with any other vaccines. Side effects from vaccination are rare. Mild and temporary local reactions, such as pain, erythema and induration, may appear 2448 hours after administration. Moderate systemic reactions such as fever and irritability may be present in 1030% of vaccines. Anaphylactic reactions after vaccination are rare. General contraindications to vaccination apply to all meningococcal vaccines. There is no contraindication for meningococcal polysaccharide vaccines during pregnancy when the benet of vaccination outweighs potential risks to the fetus. Conjugate vaccines are no longer contraindicated in individuals with history of Guillain-Barr syndrome.
short-term efcacy and antibody values decreased markedly within 12 months of immunization.37 Meningococcal disease occurs soon after mucosal acquisition of the bacteria. Once serum antibody values wane, the ability of an immunized person to mount a memory antibody response upon exposure to a pathogenic group C strain may not be rapid enough to prevent disease. Data showing decreased vaccine effectiveness between 1 and 4 years after immunization of infants and toddlers, at a time when they can mount robust memory antibody responses, suggest that serum antibody persistence is more important in protection than memory.38 Enzyme-linked immunosorbent assay tests are also used to determine the serogroup C meningococcal polysaccharide specic IgG, which can be expressed as geometric mean titers or geometric mean antibody concentrations. Immunogenicity studies likely predict short-term effectiveness; however, their ability to determine long-term effectiveness is uncertain as antibody levels decline postvaccination within 68 months. It is hoped that higher postvaccination titers will correlate with a longer duration of protection, but evidence supporting this hypothesis is lacking.39
WHAT IS THE CORRELATE OF PROTECTION, THE EFFICACY AND THE HERD PROTECTION GENERATED BY THE VACCINES?
Serum antibodies confer protection against IMD by activating complement-mediated bacteriolysis and by enhancing phagocytosis (opsonic activity).34 In the 1960s, Goldschneider et al34 using a serum bactericidal activity assay (SBA) found that military recruit with a titer 1:4 who were exposed during a group C meningococcal epidemic did not develop disease while virtually all cases occurred in individuals whose SBA titers were <1:4. In addition, SBA was rarely detected in children 2 months to 2 years of age, the age group with the highest incidence of disease. In contrast, many adults, in whom disease was rare, had SBA titers 1:4 measured against group A, B and C strains. It was also demonstrated that the meningococcal carrier state is an immunizing process and antibodies can be identied in many individuals within 2 weeks of colonization. The Goldschneider study demonstrating a correlation between the SBA titer and protection, used human complement in the assay (hSBA). When measured with human complement, a SBA titer 1:4 is generally considered protective for serogroup C and A. Measurements of SBA are likely to be useful for evaluating immunization schedules for OMV vaccines,35 but there are no conrmed immunological correlates of protection for serogroups Y, X and W. As it is now difcult to nd sufcient amounts of human sera that lack antimeningococcal antibodies to serve as a source of exogenous complement, many laboratories now use infant rabbit serum (rSBA) because it is widely available and can be shared among laboratories for standardization of the assay.36 There are 2 possible approaches to establish a serological correlate of protection for a vaccine. One is based on immunogenicity data from individuals and the other is from a vaccinated population as a whole. To validate the use of rSBA as a correlate of protection in younger age groups, a population-based approach was selected in a UK study after the introduction of conjugate MenC vaccines. One month after vaccination, a rSBA threshold of 1:8 correlated best with observed efcacy, but this only applied to 2013 Lippincott Williams & Wilkins
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a vaccine effectiveness study demonstrate waning effectiveness, and many adolescents are not protected 5 years after vaccination. Results from a case control study in the United States among individuals 1023 years of age, demonstrated 77% vaccine effectiveness for serogroup C (95% condence interval (CI): 1494%) and 88% vaccine effectiveness for serogroup Y (95% CI: 23 to 99%). These results indicate that vaccine effectiveness wanes over time when assessed up to 5 years postvaccination. Therefore, in the United States, a booster is now recommended for adolescents 5 years after the rst dose.44
identied in Brazil, potential coverage of 4CMenB was 80.8% (95% CI: 70.794.9%), consistent with the results found in European countries.51
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coadministration with other infant vaccines should be explored. Alternative immunization schedules and partnership between private manufacturers and public institutions should be considered. The Consensus Panel believes that the implementation of the above recommendations will greatly reduce the adverse impact of IMD. REFERENCES
1. Sfadi MA, Cintra OA. Epidemiology of meningococcal disease in Latin America: current situation and opportunities for prevention. Neurol Res. 2010;32:263271. 2. Nelson KE, Sifakis F. Surveillance. In: Nelson KE, Masters Williams C, eds. Infectious Disease Epidemiology: Theory and Practice. 2nd ed. Sudbury: Jones and Bartlett Publishers; 2007:119146. 3. Harrison LH, Pelton SI, Wilder-Smith A, et al. The global meningococcal initiative: recommendations for reducing the global burden of meningococcal disease. Vaccine. 2011;29:33633371. 4. Ibarz-Pavon AB, Lemos AP, Gorla MC, et al. Laboratory-based surveillance of Neisseria meningitidis isolates from disease cases in Latin American and Caribbean countries, SIREVA II 20062010. PLoS One. 2012;7:e44102. 5. Lemos APS, Gorla MO, Galhardo M, et al. Rapid changing in trends of meningococcal disease in Brazil from 2000 to 2010. In: Presentation/ Congress; Sao Paulo: National Reference Laboratory for Meningitis, Bacteriology Branch, Adolfo Lutz Institute. 6. Bryant PA, Li HY, Zaia A, et al. Prospective study of a real-time PCR that is highly sensitive, specic, and clinically useful for diagnosis of meningococcal disease in children. J Clin Microbiol. 2004;42:29192925. 7. Wang X, Theodore MJ, Mair R, et al. Clinical validation of multiplex realtime PCR assays for detection of bacterial meningitis pathogens. J Clin Microbiol. 2012;50:702708. 8. Corless CE, Guiver M, Borrow R, et al. Simultaneous detection of Neisseria meningitidis, Haemophilus inuenzae, and Streptococcus pneumoniae in suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol. 2001;39:15531558. 9. Bottomley MJ, Serruto D, Sfadi MA, et al. Future challenges in the elimination of bacterial meningitis. Vaccine. 2012;30(suppl 2):B78B86. 10. Jolly K, Stewart G. Epidemiology and diagnosis of meningitis: results of a ve-year prospective, population-based study. Commun Dis Public Health. 2001;4:124129. 11. Sacchi CT, Fukasawa LO, Gonalves MG, et al.; So Paulo RT-PCR Surveillance Project Team. Incorporation of real-time PCR into routine public health surveillance of culture negative bacterial meningitis in So Paulo, Brazil. PLoS One. 2011;6:e20675. 12. Chacon-Cruz E, Sugerman DE, Ginsberg MM, et al. Surveillance for inva sive meningococcal disease in children, US-Mexico border, 2005-2008. Emerg Infect Dis. 2011;17:543546. 13 Espinosa de los Monteros LE, Jimenez-Rojas LV, Matias San Juan NA, et al. Grupo Mexicano de Trabajo en Enfermedad Meningococcica. Unusual increase in meningococcal disease associated with serogroup C in Mexico City. Paper presented at: 7th World Congress on Pediatric Infectious Diseases (WSPID); November 1619, 2011; Melbourne, Australia. 14. Mossong J, Hens N, Jit M, et al. Social contacts and mixing patterns relevant to the spread of infectious diseases. PLoS Med. 2008;5:e74. 15. Diggle MA, Clarke SC. Molecular methods for the detection and characteri zation of Neisseria meningitidis. Expert Rev Mol Diagn. 2006;6:7987. 16 Jolley KA, Gray SJ, Suker J, et al. Methods for typing of meningococci. In: Frosch M, Maiden MCJ, eds. Handbook of Meningococcal Disease: Infection Biology, Vaccination, Clinical Management. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co.; 2006:3751. 17. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev. 2006;19:142164. 18. Roberts J, Greenwood B, Stuart J. Sampling methods to detect carriage of Neisseria meningitidis; literature review. J Infect. 2009;58:103107. 19. Christensen H, May M, Bowen L, et al. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:853861. 20 Espinosa de los Monteros LE, Aguilar-Ituarte F, Jimnez-Rojas LV, et al. Prevalence of Neisseria meningitidis carriers in children under ve years of age and teenagers in certain populations of Mexico City. Salud Pblica de Mx. 2009;51:114118. 21. Stephens DS. Biology and pathogenesis of the evolutionarily successful, obligate human bacterium Neisseria meningitidis. Vaccine. 2009;27(suppl 2):B71B77.
RECOMMENDATIONS
(1) There is a clear need for better surveillance systems across the region. The establishment of sentinel-based active surveillance systems, along with passive systems, incorporating population-based data, will be crucial to ensure accurate estimates of disease burden. Standardized passive and active surveillance systems, with quality information, should be developed to acknowledge the burden of the disease, including incidence, case-fatality rates and prevalent serogroups in Latin America. Carriage studies are mandatory. (2) Countries should make greater use of the PCR assays to improve the sensitivity of diagnosis and surveillance of IMD. (3) All efforts should be made to provide adequate infrastructure conditions for early diagnosis and treatment and to reduce case-fatality rates and morbidity associated to meningococcal disease. (4) Development of vaccines with broader coverage and more immunogenic in young infants is needed. (5) Prevention strategies should include immunization of young infants and catch-up in children and adolescents, but these policies needs to be tailored according to individual country, cost-effectiveness studies and knowledge of disease burden, before initiating widespread national immunization programs. (6) Due to the crowded infant immunization schedule, the development of combined meningococcal vaccines and the 2013 Lippincott Williams & Wilkins
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22. Aguilera JF, Perrocheau A, Meffre C, et al.; W135 Working Group. Outbreak of serogroup W135 meningococcal disease after the Hajj pilgrimage, Europe, 2000. Emerg Infect Dis. 2002;8:761767. 23. Efron AM, Sorhouet C, Salcedo C, et al. W135 invasive meningococcal strains spreading in South America: signicant increase in incidence rate in Argentina. J Clin Microbiol. 2009;47:19791980. 24 Meningococcal vaccines: WHO position paper. Wkly Epidemoil Rec [World Health Organization web site]. November 18, 2011;86:521540. Available at: http://www.who.int/wer/2011/wer8647/en/index.html. Accessed August 8, 2013. 25. Trotter CL, Maiden MC. Meningococcal vaccines and herd immunity: les sons learned from serogroup C conjugate vaccination programs. Expert Rev Vaccines. 2009;8:851861. 26 Licensure of a meningococcal conjugate vaccine for children aged 2 through 10 years and updated booster dose guidance for adolescents and other persons at increased risk for meningococcal disease -- Advisory Committee on Immunization Practices (ACIP), 2011. Morb Mortal Wkly Rep [Centers for Disease Prevention and Control web site]. August 5, 2011;60:10181019. 27. Halperin SA, Gupta A, Jeanfreau R, et al. Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 210 years of age. Vaccine. 2010;28:78657872. 28. Black SB, Plotkin SA. Meningococcal disease from the public health policy perspective. Vaccine. 2012;30(suppl 2):B37B39. 29. Frasch CE, Mocca LF, Karpas AB. Appearance of new strains associated with group B meningococcal disease and their use for rapid vaccine development. Antonie Van Leeuwenhoek. 1987;53:395402. 30. Granoff DM. Review of meningococcal group B vaccines. Clin Infect Dis. 2010;50(suppl 2):S54S65. 31. Halperin SA, Bettinger JA, Greenwood B, et al. The changing and dynamic epidemiology of meningococcal disease. Vaccine. 2012;30(suppl 2):B26B36. 32. Santolaya ME, ORyan ML, Valenzuela MT, et al.; V72P10 Meningococcal B Adolescent Vaccine Study group. Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebocontrolled study. Lancet. 2012;379:617624. 33. Richmond PC, Marshall HS, Nissen MD, et al.; 2001 Study Investigators. Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012;12:597607. 34. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. II. Development of natural immunity. J Exp Med. 1969;129:13271348. 35. Holst J, Feiring B, Fuglesang JE, et al. Serum bactericidal activity corre lates with the vaccine efcacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease. Vaccine. 2003;21:734737. 36. Jodar L, Cartwright K, Feavers IM. Standardisation and validation of sero logical assays for the evaluation of immune responses to Neisseria meningitidis serogroup A and C vaccines. Biologicals. 2000;28:193197. 37. Andrews N, Borrow R, Miller E. Validation of serological correlate of pro tection for meningococcal C conjugate vaccine by using efcacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10:780786. 38. Borrow R, Goldblatt D, Andrews N, et al. Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United kingdom. J Infect Dis. 2002;186:13531357.
39. Gheesling LL, Carlone GM, Pais LB, et al. Multicenter comparison of Neisseria meningitidis serogroup C anti-capsular polysaccharide antibody levels measured by a standardized enzyme-linked immunosorbent assay. J Clin Microbiol. 1994;32:14751482. 40. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningo coccal serogroup C conjugate vaccine 4 years after introduction. Lancet. 2004;364:365367. 41. Maiden MC, Stuart JM; UK Meningococcal Carraige Group. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet. 2002;359:18291831. 42. Maiden MC, Ibarz-Pavn AB, Urwin R, et al. Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity. J Infect Dis. 2008;197:737743. 43 Safadi MAP, Liphaus B, Okay MIG, et al. Early impact of meningococcal C conjugate vaccination program on disease trends in Sao Paulo, Brazil. Abstract presented at: 30th Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID); May 812, 2012. Thessaloniki, Greece. 44 Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep [Centers for Disease Prevention and Control web site]. March 22, 2013;62. 45 Padron FS, Huergo CC, Gil VC, et al. Cuban meningococcal BC vaccine: Experiences & contributions from 20 years of application. MEDICC Rev. 2007;9:1621. 46. de Moraes JC, Perkins BA, Camargo MC, et al. Protective efcacy of a serogroup B meningococcal vaccine in Sao Paulo, Brazil. Lancet. 1992;340:10741078. 47. Kelly C, Arnold R, Galloway Y, et al. A prospective study of the effec tiveness of the New Zealand meningococcal B vaccine. Am J Epidemiol. 2007;166:817823. 48. Borrow R, Carlone GM, Rosenstein N, et al. Neisseria meningitidis group B correlates of protection and assay standardizationinternational meeting report Emory University, Atlanta, Georgia, United States, 16-17 March 2005. Vaccine. 2006;24:50935107. 49. Vipond C, Care R, Feavers IM. History of meningococcal vaccines and their serological correlates of protection. Vaccine. 2012;30(suppl 2):B10B17. 50. Dull PM, McIntosh ED. Meningococcal vaccine developmentfrom gly coconjugates against MenACWY to proteins against MenBpotential for broad protection against meningococcal disease. Vaccine. 2012;30(suppl 2):B18B25. 51 Lemos AP, et al. Presented at: 19th International Pathogenic Neisseria Conference (IPNC). September 914, 2012. Wrzburg, Germany. Poster P272. 52. Sfadi MA, McIntosh ED. Epidemiology and prevention of meningococ cal disease: a critical appraisal of vaccine policies. Expert Rev Vaccines. 2011;10:17171730. 53. Salisbury DM, Beverley PC, Miller E. Vaccine programmes and policies. Br Med Bull. 2002;62:201211. 54. de Soarez PC, Sartori AM, de Andrade Lagoa Nbrega L, et al. Cost effectiveness analysis of a universal infant immunization program with meningococcal C conjugate vaccine in Brazil. Value Health. 2011;14:1019 1027. 55 AAP. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics. 2005;116:496505.
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